The purpose of this project is to elucidate the molecular and immune pathogenesis of squamous cell neoplasms of the upper aerodigestive tract, and to enable the development of approaches for molecular and immune therapy for these disorders. Human and murine squamous cell carcinoma cell line models have been developed and used to identify genes that are differentially expressed with tumor progression using molecular and immune assays. Proinflammatory cytokines, related signal transduction pathway molecules, and immediate early transcription factor genes have been shown to be overexpressed or activated with tumor progression, and are associated with aggressive growth and metastasis. The function of these candidate genes following overexpression or inhibition by transfection of tumors with dominant negative constructs has been the subject of recent investigations to identify potential targets for molecular and immune therapy. Based upon the hypothesis that the cytokines produced by these neoplasms disrupt the immune response, studies of antigen recognition and activation of protective immune responses following treatment with recombinant and virally transduced immunoregulatory cytokines have been ongoing. The first syngeneic murine model of oral carcinoma for study of immune therapy was developed in collaboration with investigators from the University of Louisville. These studies have resulted in the identification of three cytokines with anti-tumor activity. The cellular mechanisms of immunity and molecular structure of the antigens recognized will be the subject of future investigations to determine whether therapies or vaccines using these cytokines may be suitable for human clinical trials.